PROJECT SUMMARY Gain-of-function mutations in the genes encoding or age related modifications of the cardiac isoform of the voltage-gated sodium channel have been associated with the Long-QT Syndrome Type 3 (LQT3) and heart failure. The genetic form of sodium channel gain of function disease LQT3 represents an exemplar for elucidating the role sodium channels play in sudden death independent of systemic remodeling. The principal issue that will be addressed in this application is the role intercellular coupling plays in translating a cellular pathologic response into a tissue level response that causes sudden cardiac death. In short, if cells electrically communicate only by gap junctional coupling, then statistically the chance of sudden death should be low and only occur after substantial gap junction loss of function. However, if cells can also communicate via electric fields generated in very narrow spaces between cells (ephaptic coupling), then pathologic activity should manifest during substantial ephaptic remodeling. Additionally, symptoms of LQT3 do not manifest until sometime during or after puberty, suggesting that young organisms are protected against life-threatening cardiac events by some type of age related remodeling. Since gap junctions redistribute around cells, but do not necessarily decrease expression, the gap junction coupling hypothesis remains speculative at best. However, since the determinants of cellular excitability and ephaptic coupling change with age, the hypothesis that ephaptic coupling modulates sudden death during gain-of-sodium function requires investigation. Upon successful completion of these aims, we will produce new theoretical underpinnings of LQT3 and heart failure that will help design new early detection tests and suggest new treatments during disease progression.